Pentavalent arsenate transport by zebrafish phosphate transporter NaPi-IIb1.
Arsenate is a pentavalent form of arsenic that shares similar chemical properties to phosphate. It has been shown to be taken up by phosphate transporters in both eukaryotic and prokaryotic microbes such as yeast and Escherichia coli. Recently, the arsenate uptake in vertebrate cells was reported to be facilitated by mammalian type II sodium/phosphate transporter with different affinities. As arsenate is the most common form of arsenic exposure in aquatic system, identifying the uptake pathway of arsenate into aquatic animals is a crucial step in the elucidation of the entire metabolic pathway of arsenic. In this study, the ability of a zebrafish phosphate transporter, NaPi-IIb1 (SLC34a2a), to transport arsenate was examined. Our results demonstrate that a type II phosphate transporter in zebrafish, NaPi-IIb1, can transport arsenate in vitro when expressed in Xenopus laevis oocytes. NaPi-IIb1 mediates a high-affinity arsenate transport, with a K(m) of 0.22 mM. The natural substrate of NaPi-IIb1, dibasic phosphate, inhibits arsenate transport. Arsenate transport via NaPi-IIb1 is coupled with Na(+) and exhibits sigmoidal kinetics with a Hill coefficient of 3.24 ± 0.19. Consistent with these in vitro studies, significant arsenate accumulation is observed in all examined zebrafish tissues where NaPi-IIb1 is expressed, particularly intestine, kidney, and eye, indicating that zebrafish NaPi-IIb1 is likely the transport protein that is responsible for arsenic accumulation in vivo.


The limitations of intimate samples in sexual offences.
This article reviews the problems of sampling and interpretation of scientific findings from samples taken by doctors during their examination of victims and suspects in sexual offences. The problems which may be encountered with vaginal, anal, oral and penile swabs are highlighted. These include contamination between samples and the consequences thereof. The responsibilities of the medical examiner, the investigating police officer and the scientist are stressed. Surveys of results stored in a database and case examples are used to illustrate the problems.


Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations.
TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease. To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations. Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non-superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls. Main Outcome Measure We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD. The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography. Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD cosegregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.


Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes.
Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes during the development of obesity. However, it remains unclear whether palmitate directly impacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstream metabolic outputs. Here we presented evidence that the molecular clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhibits the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein interaction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes.


The determination of the effective attenuation coefficient from effective organ depth and modulation transfer function in gamma camera imaging.
Absolute measurement of activity implies a determination of effective depths and effective attenuation coefficients. In order to define restoration filters, it is necessary to measure the transfer function, i.e. position a line source at an effective depth for the specific measurement situation. A phantom was designed which can simulate an organ with a certain thickness at a certain depth. The phantom was used to measure transfer functions and a comparison was made with transfer functions from a line source to determine effective depths. Effective attenuation coefficients were calculated for 99mTc, 111In and 201Tl for different organ thicknesses and depths of simulated organs. The effective attenuation coefficient for 99mTc was found to be 0.124 +/- 0.006 cm-1, in good agreement with previously published values. For 111In, the attenuation coefficient decreased with the depth of an organ due to the use of two energy windows in the measurements and a corresponding change in mean photon energy by depth. For 201Tl, the attenuation coefficient decreased with increasing organ thickness due to the increasing fraction of scattered radiation in the 40% energy window used. Using attenuation coefficients of 0.124, 0.184 and 0.11 cm-1 for 99mTc, 201Tl and 111In respectively, the derived equations can be used to calculate the position of a conventional line source for measurements of transfer functions for a specific organ with a certain thickness at a certain depth for definition of different types of restoration filter.


A randomized-controlled pilot study comparing ICD implantation with and without intraoperative defibrillation testing in patients with heart failure and severe left ventricular dysfunction: a substudy of the RAFT trial.
The need to perform defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion is controversial. In the absence of randomized trials, some regions now perform more than half of ICD implants without DT. During the last year of enrolment in the Resynchronization for Ambulatory Heart Failure Trial, a substudy randomized patients to ICD implantation with versus without DT. Among 252 patients screened, 145 were enrolled; 75 randomized to DT and 70 to no DT. Patients were similar in terms of age (65.9 ± 9.3 years vs 67.9 ± 8.9 years); LVEF (24.7 ± 4.6% vs 23.6 ± 4.6%), QRS width (154.8 ± 23.5 vs 155.8 ± 23.6 ms), and history of atrial fibrillation (5% vs 6%). All 68 patients in the DT arm tested according to the protocol achieved a successful DT (≤25 J); 96% without requiring any system modification. No patient experienced perioperative stroke, myocardial infarction, heart failure (HF), intubation or unplanned ICU stay. The length of hospital stay was not prolonged in the DT group: 20.2 ± 26.3 hours versus 21.3 ± 23.0 hours, P = 0.79. One patient in the DT arm had a failed appropriate shock and no patient suffered an arrhythmic death. The composite of HF hospitalization or all-cause mortality occurred in 10% of patients in the no-DT arm and 19% of patients in the DT arm (HR = 0.53, 95% CI: 0.21-1.31, P = 0.14). In this randomized trial, perioperative complications, failed appropriate shocks, and arrhythmic death were all uncommon regardless of DT. There was a nonsignificant increase in the risk of death or HF hospitalization with DT.


Topographic mapping--the olfactory system.
Sensory systems must map accurate representations of the external world in the brain. Although the physical senses of touch and vision build topographic representations of the spatial coordinates of the body and the field of view, the chemical sense of olfaction maps discontinuous features of chemical space, comprising an extremely large number of possible odor stimuli. In both mammals and insects, olfactory circuits are wired according to the convergence of axons from sensory neurons expressing the same odorant receptor. Synapses are organized into distinctive spherical neuropils--the olfactory glomeruli--that connect sensory input with output neurons and local modulatory interneurons. Although there is a strong conservation of form in the olfactory maps of mammals and insects, they arise using divergent mechanisms. Olfactory glomeruli provide a unique solution to the problem of mapping discontinuous chemical space onto the brain.


Haemopoietic origin of myofibroblasts formed in the peritoneal cavity in response to a foreign body.
This study utilized both in vivo and in vitro techniques to investigate whether cells of bone marrow origin can differentiate into smooth muscle-like cells (myofibroblasts) with contractile filaments and proteins. Female C57BL/6 mice expressing the Ly5.2 antigen on the surface of their haemopoietic cells had four pieces of silastic tubing (3 x 0.5 mm outer diameter) or boiled blood clot (2-3 mm diameter) placed in their peritoneal cavity. After 3, 5, 7 and 14 days (n = 4/group) the implants were removed and those that had remained free-floating were processed for light microscopy, immunohistochemistry and electron microscopy. In the first 3-5 days, rounded cells adhered to the entire surface of the tubing then flattened. These cells stained with fluoresceinated antibodies to Ly5.2 showing that they were derived from haemopoietic cells. By 14 days the cells had become elongated and multilayered in a collagen matrix, forming a thick tissue capsule around the tubing or boiled clot. They contained contractile filaments and stained with antibodies to alpha-smooth muscle actin but no longer stained for Ly5.2. A separate set of female C57BL/6 Ly5.2 mice were X-irradiated to destroy bone marrow then immediately transfused with 10(6) nucleated bone marrow cells taken from the femur and tibia of a congenic strain of male mice expressing the Ly5.1 allele. Eight of the female mice with successful engraftment (80-99%) had silastic tubing implanted in the peritoneal cavity. After 14 days, in situ hybridization with Y chromosome probe confirmed the male donor, and thus bone marrow, origin of the elongated cells that formed the capsule. In vitro studies showed that cells of the murine macrophage cell lines RAW 264.7 and J774 express alpha-smooth muscle actin after exposure to the cytokine gamma-interferon in vitro. These data show that bone marrow-derived cells can differentiate into smooth muscle-like cells and raises the possibility that blood-derived cells may contribute to the development of fibro-proliferative vascular diseases such as atherosclerosis.


Soluble Methane Monooxygenase.
Aerobic life is possible because the molecular structure of oxygen (O2) makes direct reaction with most organic materials at ambient temperatures an exceptionally slow process. Of course, these reactions are inherently very favorable, and they occur rapidly with the release of a great deal of energy at high temperature. Nature has been able to tap this sequestered reservoir of energy with great spatial and temporal selectivity at ambient temperatures through the evolution of oxidase and oxygenase enzymes. One mechanism used by these enzymes for O2 activation has been studied in detail for the soluble form of the enzyme methane monooxygenase. These studies have revealed the step-by-step process of O2 activation and insertion into the ultimately stable C-H bond of methane. Additionally, an elegant regulatory mechanism has been defined that enlists size selection and quantum tunneling to allow methane oxidation to occur specifically in the presence of more easily oxidized substrates.


Percutaneous treatment of an iatrogenic femoral arteriovenous fistula from an accessory arterial branch: a case report and review of the literature.
Vascular access-related complications are an important consideration in patients undergoing cardiac catheterisation. Patients with CHD are increasingly undergoing percutaneous treatment for suitable procedures as an alternative, less invasive option to surgical intervention. As such, recognition and treatment of these complications are becoming increasingly important. We present a case of a patient with repaired Tetralogy of Fallot who developed a femoral arteriovenous fistula and femoral artery pseudoaneurysm arising from an accessory arterial branch following percutaneous Harmony valve implantation, both of which were treated endovascularly with placement of a stent.


The insertion technique of translaminar screws in the thoracic spine: computed tomography and cadaveric validation.
Translaminar screws can be a good salvage technique in some cases of severe deformities, infection, tumor, osteoporosis, and revision cases with altered anatomy. To our knowledge, the insertion technique for translaminar screws in the thoracic spine has not been studied. To suggest a safe insertion technique of translaminar screws in the thoracic spine. A cadaveric study. Fifteen cadaveric spines were harvested from T1 to T12, and 1-mm computed tomography (CT) scans and three-dimensional reconstructions were obtained to rule out any bony anomaly. Eleven of the cadaveric spines were separated at each level from T1 to T12 (Group S) and four were not separated (Group N-S). Translaminar screws were inserted into every level along the trajectories proposed by the previous studies. The screw diameter was determined based on the reference article. For T1-T6, the screw diameter selected was 4 mm, and for T7-T12, a 3.5-mm diameter screw was used instead. The entry point for the 1° screw was at a distance equal to the diameter of the desired screw above the inferior margin of the spinolaminar junction. To create the trajectory, a drill guide was inserted at the entry point and directed toward the middle portion of the base of the transverse process of the contralateral side and was followed carefully to not break the inner/outer cortex of the lamina. The length of the drilled hole, representing the trajectory of the screw made by the drill guide, was measured, and the 1° screws were inserted according to the length measured. The entry point for the 2° screw was at a distance equal to the diameter of the screw below the superior margin of the base of the spinous process and lamina junction. The drill guide was pointed toward the inferior angle of the contralateral junction of the rib and the vertebra along the slope of the contralateral lamina. The 2° screw was inserted in the same manner as previously described. The 2° screw diameter was downsized if there was not enough space because of the 1° screw. For each vertebra from the 11 separated cadaveric spines, inner or outer cortex breakage was checked visually. For the remaining four nonseparated spines, CT scans were used to find any inner or outer cortex breakage. Thirty-three vertebral levels were abandoned from Group S because of altered anatomy (eg, fusion, fracture during separation, anatomical anomaly of having only 11 thoracic spine segments). Out of 147 vertebral levels, there was no vertebra that did not allow screw insertion. No specimen required using smaller diameter 2° screw because of blockage of the 1° screw. There was no cortical breakage by the screws in Group S. In Group N-S, CT scan showed four inner cortex breakages and three outer cortex breakages, all of which were slight cortical breakages. There were no facet injuries due to the screws in Group N-S. There was no blockage of the ribs during screw placement in all specimens, and the drill guide could lean against the rib for guidance because the angle of the rib and the opposite lamina tended to be the same. Translaminar screws can be inserted relatively safely in the thoracic spine. For the 1° translaminar screw, the entry point is at a distance equal to the diameter of the desired screw superior to the inferior margin of the lamina-spinous process junction. The trajectory should be targeted toward the center of the base of the contralateral transverse process. For the 2° translaminar screw, the entry point is at a distance equal to the diameter of the desired screw below the superior margin of lamina-spinous process junction, and the target is the inferior angle of the junction of the rib and vertebra on the contralateral side.


Morphology of bacterial flora in root canals associated with apical abscesses.
Apical abscess is an inflammatory process in the peri-radicular tissues caused by biofilms in the necrotic root canal systems. Therefore, a comprehensive analysis of the bacterial colonization is required for a better understanding of the pathogenesis. This study aimed to investigate the patterns of bacterial infection of root canals of teeth with apical abscesses and to determine whether histological and microbiological findings correlated with clinical conditions. Eighteen samples from 18 teeth with apical pathological lesions were analyzed. Nine patients with acute apical abscesses experienced severe pain, and nine patients were asymptomatic with a sinus tract. After extraction, each affected root was divided into two halves. One half was processed for histobacteriologic analysis and examined using light microscopy, and the other half was analyzed using scanning electron microscopy (SEM) to determine the patterns of microbial colonization of the root canals. The appearance of each sample subjected to SEM was consistent with the histobacteriologic findings despite the presence or absence of clinical symptoms. Intraradicular biofilms comprising cocci, rods, and/or filaments of amorphous materials were observed in the apical third of the main root canals in all samples. The bacterial biofilms covering the main root canal walls also penetrated the dentinal tubules to varying depths. The morphologies of biofilms varied, and a unique pattern of intraradicular infection was not identified. Intraradicular infections formed complex and variable multispecies biofilms and their presence did not correlate with clinical symptoms.


Proposal for a Radiological Classification System for Carpo-Metacarpal Joint Dislocations with or without Fractures.
Introduction: Though complex injuries like CarpoMetacarpal (CMC) Joint dislocations represent only 1% of all hand injuries, they have disabling impact on the functional status of patient. There are no reports in the literature classifying disabling complex injuries like CMC joint dislocations presumably because of low incidence. We propose a new classification through retrospective analysis of patients, along with literature search. Materials and Methods: A new classification system has been proposed and designed at our clinical unit and applied to eight patients with CMC joint dislocations. All patients were treated with open reduction with Kirschner wire fixation. At follow-up all these patients were analysed for radiographic assessments and functional scores. Results: The proposed classification identifies three types of dislocations and an additional complex category to supplement any basic type. The direction of dislocation describes the types as Type A: Dorsal, Type B: Volar and Type C: Divergent. Among the eight patients in our study, we had two of Type A, two Type B, three Type B.1, one Type C. 1. These patients had average follow-up of 18 months. The quick DASH score improved from 75.76 at 6 weeks to 1.9 at 18 months. We also did intra-observer and inter-observer reliability which scored 1. Conclusion: Our proposal is a reproducible, simple, comprehensive and practical classification, easily remembered and communicated among colleagues. It is clinically relevant as it helps us in planning surgical management and prognostic evaluation.


Cytotoxic and immunoregulatory function of intestinal lymphocytes in Chlamydia trachomatis proctitis of nonhuman primates.
To study the role of natural killer cells and immunoregulatory T cells in the pathogenesis of proctitis due to Chlamydia trachomatis (L2 serovar), lymphocytes were obtained from the rectal mucosa and other sites of nonhuman primates and studied by using phenotypic and functional assays. In animals with lymphogranuloma venereum (LGV) proctitis, the percentage of lymphocytes with the natural killer cell phenotype (Leu-11+) was not significantly higher at any site in LGV infection, and natural killer cell function of lymphocytes isolated from the rectum was lower during LGV infection. This was not due to the suppressive effect of factors in serum, rectal lymphocytes, or LGV elementary bodies. In studies of regulatory T cells, the Leu-3+/Leu-2+ ratio was lower in the peripheral blood and the spleen during LGV infection, but the ratio did not decrease in lamina propria T cells. Both peripheral blood and rectal lymphocytes had higher helper T-cell function for polyclonal immunoglobulin G (IgG) synthesis in pokeweed mitogen-stimulated cultures 2 weeks following LGV infection. Increased suppressor T-cell function for pokeweed mitogen-stimulated IgG synthesis was found only in the peripheral blood of animals 2 weeks after infection, but not in isolated rectal lymphocytes. These results indicate that in LGV proctitis natural killer cells are not an important component of the inflammatory infiltrate at the site of infection, and helper T-cell function increases in peripheral blood and rectal lymphocytes.


Nucleic acid delivery and nanoparticle design for COVID vaccines.
Nucleic acid therapeutics offer a new paradigm to rapidly respond to global health problems. The versatility of nucleic acids, especially in RNA therapies, provides the ability to tune levels of specific protein expression, achieving downregulation through short interfering RNA (siRNA) or upregulation by messenger RNA (mRNA) administration. Recent advances in the development of delivery vehicles, including nonviral nanoparticles are crucial to overcome the innate barriers to nucleic acid delivery. Toward this end, current clinical approaches have utilized mRNA and lipid nanoparticles (LNPs) to address the COVID-19 pandemic through novel vaccine strategies, producing efficacious vaccines within one year of sequencing the SARS-CoV-2 genome. Here, we review fundamental concepts required to achieve successful nucleic acid delivery, including the design of LNP systems optimized for mRNA vaccine applications.


Dietary Intake and Menstrual Health among Acrobatics and Tumbling NCAA Division I Student-Athletes.
Acrobatics & Tumbling (A&T) is an emerging sport in the National Collegiate Athletic Association that lacks research regarding the dietary intake and health of A&T student-athletes (A&Tsa). This study assessed the dietary intake adequacy, estimated energy availability (EA), self-reported menstrual health, and body composition of A&Tsa. Twenty-four female A&Tsa participated during week 8 of the preseason (11 top: Age= 20.1 ± 0.9 years; BMI= 22.1 ± 1.7 kg/m2; 13 base: Age= 19.5 ± 1.3 years; BMI= 26.2 ± 2.7 kg/m2). Total energy intake (TEI) and macronutrient intakes were assessed via a paper-based 3-day dietary recall. Resting Metabolic Rate [RMR = 500 + 22 * fat-free mass (FFM)] and energy availability [EA = (TEI - exercise energy expenditure)/FFM)] were estimated; and LEAF-Q assessed menstrual health. Body composition was measured using Dual-Energy X-Ray Absorptiometry. Macronutrient intakes and EA were compared to sports nutrition recommendations (carbohydrate: 6-10 g/kg; protein: 1.2-2.0 g/kg) and the Acceptable Macronutrient Distribution Range (carbohydrate: 45-65%; protein: 10-35%; fat: 20-35%). TEI was 1753 ± 467 kcal (top) and 1980 ± 473.8 kcal (base). A total of 20.8% of A&Tsa failed to meet RMR with TEI, with a higher prevalence in the top (-266 ± 219.2 kcal, n = 3) vs. base (-414.3 ± 534.4 kcal, n = 2) A&Tsa. Top and base A&Tsa had both low EA (28.8 ± 13.4 kcals·FFM-1; 23.8 ± 9.5 kcals·FFM-1) and inadequate carbohydrate intake averages (4.2 ± 1.3 g/kg; 3.5 ± 1.1 g/kg, p < 0.001), respectively. A total of 17% of A&Tsa reported secondary amenorrhea, with a higher prevalence in the top (27.3%, n = 3) vs. the base (7.7%, n = 1). TEI and carbohydrate intake of the majority of A&Tsa were below recommendations. Sports dietitians should encourage and educate A&Tsa about following an adequate diet that meets energy and sports-specific macronutrient needs.


Generalized methods and strategies for modeling and optimizing the optics of 3D head-mounted light field displays.
An integral-imaging based light field head-mounted display, which typically renders a 3D scene by reconstructing the directional light rays apparently emitted by the scene via an array optics, is potentially capable of rendering correct or nearly correct focus cues and therefore solving the well-known vergence-accommodation conflict problem plaguing conventional stereoscopic displays. Its true 3D image formation nature, however, imposes significant complications and the well-established optical design process for conventional head-mounted displays becomes inadequate to address the design challenges. To our best knowledge, there are no existing methods or framework that have been previously proposed or demonstrated to address the challenges of modeling and optimizing an optical system for this type of display systems. In this paper, we present novel and generalizable methodology and framework for designing and optimizing the optical performance of integral-imaging based light field head-mounted displays, including methods of system configurations, user-defined metrics for characterizing the performance of such systems, and optimization strategies unique in light field displays. A design example is further given based on the proposed design methodology for the purpose of validating the proposed design method and framework.


Mortality and cancer incidence among underground uranium miners in the Czech Republic 1977-1992.
Uranium miners in Příbram, Czech Republic were exposed to low and moderate levels of radon gas and other hazards. It is unknown whether these hazards increase the risk of mortality or cancer incidence when compared with the general Czech population. A cohort of 16 434 male underground miners employed underground for at least 1 year between 1946 and 1976, and alive and residing in the Czech Republic in 1977, were followed for mortality and cancer incidence through 1992. We compared observed deaths and cancer incidence to expectation based on Czech rates. Standardised mortality ratios (SMRs), standardised incidence ratios (SIRs) and causal mortality ratios were calculated. Underground workers in the Příbram mines had higher rates of death than expected due to all causes (SMR=1.23, 95% CI 1.20 to 1.27), all cancers (SMR=1.52, 95% CI 1.44 to 1.60), lung cancer (SMR=2.12, 95% CI 1.96 to 2.28) and extrathoracic cancer (SMR=1.41, 95% CI 1.15 to 1.77). Similar excess was observed in cancer incidence analyses, with the addition of stomach cancer (SIR=1.37, 95% CI 1.11 to 1.63), liver cancer (SIR=1.70, 95% CI 1.16 to 2.25) and rectal cancer (SIR=1.41, 95% CI 1.16 to 1.66). The SIR was elevated for all leukaemias (SIR=1.51, 95% CI 1.08 to 2.07) and for lymphatic and haematopoietic cancers combined (SIR=1.31, 95% CI 1.05 to 1.61), but results for specific subtypes were imprecise. Deaths due to hazardous mining conditions resulted in 0.33 person-years of life lost per miner. Occupational exposure to the Příbram mines resulted in excess cancers at several sites, including sites previously linked to radon and uranium exposure. Incidence analyses showed relative excess of several additional cancer subtypes.


Patient and family engagement as a potential approach for improving patient safety: A systematic review.
To obtain a comprehensive insight of the impact of patient and family engagement on patient safety and identify issues in implementing this approach. Patient and family engagement is increasingly emerging as a potential approach for improving patient safety. Mixed method multilevel synthesis. PubMed, CINAHL, Embase, and Cochrance Library (January 2009-April 2018). The review was conducted according to the principles recommended by the Cochrane Handbook for Systematic Review and in accordance with the PRISMA guidelines. Forty-two relevant studies were identified. Common intervention groups included 'direct care' and 'organization' levels with 'consultation' and 'involvement' approaches, while the 'health system' level and 'partnership and shared leadership' approaches were rarely implemented. Findings revealed positive effects of the interventions on patient safety. Most study participants expressed their willingness to engage in or support patient and family engagement. However, existing gaps and barriers in implementing patient and family engagement were identified. Future research should further focus on issuing consensus guidelines for implementing patient and family engagement in patient safety, extending the research scope for all aspects of patient and family engagement and patient safety and identifying priority areas for action that is suitable for each health facility. Policymakers should issue guidelines for implementing patient and family engagement in healthcare systems which would enable healthcare providers to implement patient and family engagement and improve patient safety appropriately and effectively.


Dynamic cross-talk analysis among TNF-R, TLR-4 and IL-1R signalings in TNFalpha-induced inflammatory responses.
Development in systems biology research has accelerated in recent years, and the reconstructions for molecular networks can provide a global view to enable in-depth investigation on numerous system properties in biology. However, we still lack a systematic approach to reconstruct the dynamic protein-protein association networks at different time stages from high-throughput data to further analyze the possible cross-talks among different signaling/regulatory pathways. In this study we integrated protein-protein interactions from different databases to construct the rough protein-protein association networks (PPANs) during TNFalpha-induced inflammation. Next, the gene expression profiles of TNFalpha-induced HUVEC and a stochastic dynamic model were used to rebuild the significant PPANs at different time stages, reflecting the development and progression of endothelium inflammatory responses. A new cross-talk ranking method was used to evaluate the potential core elements in the related signaling pathways of toll-like receptor 4 (TLR-4) as well as receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R). The highly ranked cross-talks which are functionally relevant to the TNFalpha pathway were identified. A bow-tie structure was extracted from these cross-talk pathways, suggesting the robustness of network structure, the coordination of signal transduction and feedback control for efficient inflammatory responses to different stimuli. Further, several characteristics of signal transduction and feedback control were analyzed. A systematic approach based on a stochastic dynamic model is proposed to generate insight into the underlying defense mechanisms of inflammation via the construction of corresponding signaling networks upon specific stimuli. In addition, this systematic approach can be applied to other signaling networks under different conditions in different species. The algorithm and method proposed in this study could expedite prospective systems biology research when better experimental techniques for protein expression detection and microarray data with multiple sampling points become available in the future.


Fitness and prostate cancer screening, incidence, and mortality: Results from the Henry Ford Exercise Testing (FIT) Project.
The relation between cardiorespiratory fitness (CRF) and prostate cancer is not well established. The objective of this study was to determine whether CRF is associated with prostate cancer screening, incidence, or mortality. The Henry Ford Exercise Testing Project is a retrospective cohort study of men aged 40 to 70 years without cancer who underwent physician-referred exercise stress testing from 1995 to 2009. CRF was quantified in metabolic equivalents of task (METs) (<6 [reference], 6-9, 10-11, and ≥12 METs), estimated from the peak workload achieved during a symptom-limited, maximal exercise stress test. Prostate-specific antigen (PSA) testing, incident prostate cancer, and all-cause mortality were analyzed with multivariable adjusted Poisson regression and Cox proportional hazard models. In total, 22,827 men were included, of whom 739 developed prostate cancer, with a median follow-up of 7.5 years. Men who had high fitness (≥12 METs) had an 28% higher risk of PSA screening (95% CI, 1.2-1.3) compared with those who had low fitness (<6 METs. After adjusting for PSA screening, fitness was associated with higher prostate cancer incidence (men aged <55 years, P = .02; men aged >55 years, P ≤ .01), but not with advanced prostate cancer. Among the men who were diagnosed with prostate cancer, high fitness was associated with a 60% lower risk of all-cause mortality (95% CI, 0.2-0.9). Although men with high fitness are more likely to undergo PSA screening, this does not fully account for the increased incidence of prostate cancer seen among these individuals. However, men with high fitness have a lower risk of death after a prostate cancer diagnosis, suggesting that the cancers identified may be low-risk with little impact on long-term outcomes.


Crystal-storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification.
We report a case of crystal storing histiocytosis (CSH) of the upper lip and cheek in a 51-year-old woman and review the clinicopathologic features of 80 cases in the literature. These occurred in 41 men and 39 women with a respective mean age of 59 and 61 years (range 17-81 years). Forty-six patients (58%) had localized CSH, and, of these, 16 (35%) occurred in the head and neck, with the most common site being the eye/orbit. The remaining 34 patients (42%) had generalized CSH primarily involving bone marrow, liver, lymph nodes, spleen and/or kidney. Regardless of whether the CSH was localized or generalized, the vast majority of patients (90%) had an underlying lymphoproliferative or plasma cell disorder, especially multiple myeloma, lymphoplasmacytic lymphoma, or monoclonal gammopathy of undetermined significance. In 7 cases (8.8%), the CSH was associated with a variety of benign disorders, often with an inflammatory background, and no evidence of a clonal lymphoproliferative or plasma cell disorder. Treatment and prognosis varied according to the underlying disease. A classification of CSH based on etiology and/or associated disease and chemical composition of the crystal is proposed, rare non-immunoglobulin variants of CSH are discussed, and a differential diagnosis of other potentially confusing lesions is provided.


Uniform cell-autonomous tumorigenesis of the choroid plexus by papovavirus large T antigens.
The simian virus 40 (SV40) large tumor antigen (T antigen) under its natural regulatory elements induces choroid plexus papillomas in transgenic mice. Because these tumors develop focally after several months, it has been suggested that secondary cellular alterations are required to induce a tumor in this tissue. In contrast to SV40, the related lymphotropic papovavirus early region induces rapid nonfocal choroid plexus neoplasia in transgenic mice. Here, using hybrid gene constructs, we showed that T antigen from either virus in in fact sufficient to induce these tumors. Their abilities to induce proliferative abnormalities in other tissues, such as kidney and thymus, were also indistinguishable. Differences in the rate of choroid plexus tumorigenesis reflected differences in the control regions of the two viruses, rather than differences in T antigen per se. Under SV40 regulation, expression was limited to a fraction of the choroid plexus cells prior to the formation of focal tumors. When SV40 T antigen was placed under lymphotropic papovavirus control, in contrast, expression was generally uniform in the choroid plexus and rapid expansion of the tissue ensued. We found a direct relationship between T-antigen expression, morphological transformation, and proliferation of the choroid plexus epithelial cells. Analysis of mosaic transgenic mice indicated further that T antigen exerts its mitogenic effect cell autonomously. These studies form the foundation for elucidating the role of various T-antigen subactivities in tumorigenesis.


Home Telehealth Interventions for Older Adults With Diabetes.
The purpose of this literature review was to explore home telemedicine interventions for the treatment of older adults with diabetes. Eight databases were searched for articles published between 2011 and 2016, in the English language, and in peer-reviewed journals, resulting in 1,274 relevant articles. Following review against inclusion and exclusion criteria, six articles were retained. Studies included participants with a mean age from 68 to 76.8 years and from three different countries, with either Type 1 or Type 2 Diabetes Mellitus. The articles reviewed suggest that case management, education, closed-loop feedback and communication, home telemonitoring devices or units, and motivational interviewing or coaching can effectively decrease admissions, costs per person per year, mortality, and cognitive decline in older adults with diabetes. The scarcity of high-quality studies is consistent with findings from previous systematic reviews, and highlights the need for additional investigation before applying the results in practice.


EEG-fMRI in atypical benign partial epilepsy.
Atypical benign partial epilepsy (ABPE) is a subgroup among the idiopathic focal epilepsies of childhood. Aim of this study was to investigate neuronal networks underlying ABPE and compare the results with previous electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) studies of related epilepsy syndromes. Ten patients with ABPE underwent simultaneous EEG-fMRI recording. In all 10 patients several types of interictal epileptiform discharges (IEDs) were recorded. Individual IED-associated blood oxygen level-dependent (BOLD) signal changes were analyzed in a single subject analysis for each IED type (33 studies). A group analysis was also performed to determine common BOLD signal changes across the patients. IED-associated BOLD signal changes were found in 31 studies. Focal BOLD signal changes concordant with the spike field (21 studies) and distant cortical and subcortical BOLD signal changes (31 studies) were detected. The group analysis revealed a thalamic activation. This study demonstrated that ABPE is characterized by patterns similar to studies in rolandic epilepsy (focal BOLD signal changes in the spike field) as well as patterns observed in continuous spikes and waves during slow sleep (CSWS) (distant BOLD signal changes in cortical and subcortical structures), thereby underscoring that idiopathic focal epilepsies of childhood form a spectrum of overlapping syndromes.


Modified Frailty Index Helps Predict Mortality and Ambulation Differences Between Genders and Racial Differences Following Major Lower Extremity Amputation.
Major lower extremity amputation (LEA) is associated with significant morbidity and mortality. The modified frailty index (mFI-5) has been used to predict outcomes including ambulation and mortality after LEA. It remains unknown for which patient demographics the mFI-5 is a reliable predictor. This was a retrospective review of all patients who underwent a first-time major LEA at our institution from 2015 to 2022. Patients were stratified into 2 risk groups based on their mFI-5 score: non-frail (mFI<3) and frail (mFI≥3) and assessed on outcomes. Our sample consisted of 687 patients of whom 134 (19.6%) were considered frail and 551 (80.4%) were considered non-frail. A higher mFI-5 is associated with decreased ambulation rates (OR: 0.565, P = .004), increased hospital readmission (OR: 1.657, P = .021), and increased mortality (OR: 2.101, P = .001) following major LEA. In African American patients, frail and non-frail patients differed on readmission at 90 days (P = .008), mortality at 1 year (P = .001), ambulatory status (P < .001), and prosthesis use (P = .023). In male patients, frail and non-frail patients differed on readmission at 90 days (P = .019), death at 1 year (P = .001), and ambulatory status (P = .002). In Caucasian patients and female patients, frail and non-frail patients did not differ significantly on outcomes. The mFI-5 is a valuable predictor of outcomes following major LEA, specifically in males and African American patients. Moreover, surgeons should consider using frailty status to risk stratify patients and inform treatment plans.


Radial glia phenotype: origin, regulation, and transdifferentiation.
Radial glial cells play a major guidance role for migrating neurons during central nervous system (CNS) histogenesis but also play many other crucial roles in early brain development. Being among the earliest cells to differentiate in the early CNS, they provide support for neuronal migration during embryonic brain development; provide instructive and neurotrophic signals required for the survival, proliferation, and differentiation of neurons; and may be multipotential progenitor cells that give rise to various cell types, including neurons. Radial glial cells constitute a major cell type of the developing brain in numerous nonmammalian and mammalian vertebrates, increasing in complexity in parallel with the organization of the nervous tissue they help to build. In mammalian species, these cells transdifferentiate into astrocytes when neuronal migration is completed, whereas, in nonmammalian species, they persist into adulthood as a radial component of astroglia. Thus, our perception of radial glia may have to change from that of path-defining cells to that of specialized precursor cells transiently fulfilling a guidance role during brain histogenesis. In that respect, their apparent change of phenotype from radial fiber to astrocyte probably constitutes one of the most common transdifferentiation events in mammalian development.


Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men.
The prevalence of lifestyle diseases has escalated, and effective exercise training programmes are warranted. This study tested the hypothesis that regular participation in small-sided team handball training could provide beneficial health effects on cardiovascular, skeletal, and muscular parameters in young adult untrained men. Twenty-six untrained 20-30-year-old men were randomly allocated to either a team handball training group (HG; n = 14), which completed 1.9 ± 0.3 training sessions per week over 12 weeks, or an inactive control group (CG; n = 12). Physiological training adaptations were assessed pre- and post interventions by DXA scans, blood samples, muscle biopsies, and physical tests. The average heart rate during training was equivalent to 84 ± 4% of maximal heart rate. Compared to CG, HG displayed significant increases in VO2max (11 ± 6%), proximal femur bone mineral density (2 ± 1%), whole-body bone mineral content (2 ± 1%), intermittent endurance performance (32 ± 16%), incremental treadmill test performance (16 ± 7%) and muscle citrate synthase activity (22 ± 28%) as well as decreases in total fat mass (7 ± 7%) and total fat percentage (6 ± 7%) (all p < 0.05). There were no significant changes in muscle mass, blood pressure, resting heart rate, muscle hydroxyl-acyl-dehydrogenase activity, or blood lipids (all p > 0.05). Participation in regular recreational team handball training was associated with positive cardiovascular, skeletal, and muscular adaptations, including increased maximal oxygen uptake, increased muscle enzymatic activity, and improved bone mineralization as well as lower fat percentage. These findings suggest that recreational team handball training may be an effective health-promoting activity for young adult men.


Influences of process parameters on preparation of microparticle used as a carrier system for omega - 3 unsaturated fatty acid ethyl esters used in supplementary nutrition.
Microparticles were prepared by complex coacervation to encapsulate eicosapentaenoic acid ethyl ester (EPA-EE) for incorporation into foods as a nutrition supplement. Gelatin and acacia were used in the coacervation process. With an increasing oil/polymer ratio, both yield and encapsulation rate decreased; with an increasing homogenization time, the yield remained constant while the encapsulation rate slightly increased. Several particle hardening techniques were examined and their influence on particle structure, yield and encapsulation rate were examined. Ethanol hardening was compared to cross-linking with dehydroascrobic acid with respect to both yield and encapsulation rate. The particle diameters for both formulations were similar (ethanol: 38.4 +/- 4.1 microm; cross-linking: 41.8 +/- 3.0 microm). Spray-drying of the coacervates led to the smallest particles (5.2 +/- 1.1 microm), lowest yield and encapsulation rate. All microencapsulation products were assayed for their storage stability over 4 weeks with respect to the oxidation of the encapsulated omega - 3 unsaturated fatty acid ester inside the particles. Hardening with ethanol showed the lowest amount of peroxides: particle wall cross-linking by dehydroascorbic acid and spray-drying were observed to be less protective. All microparticles were characterized for their internal structure with confocal laser scanning microscopy (CLSM) after fluorescence labelling of the polymers, in order to localize the oil phase and visualize the distribution of the polymers in the coacervates. With increasing homogenization time, the internal structure changed stepwise from a capsule structure (core/wall) towards a matrix structure. For all experiments, a homogeneous distribution for both polymers, gelatin and acacia was observed inside the particle wall. No influence of the different particle hardening procedures on the polymer distribution was found.


Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.
An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival. We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87). This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).


Interleukin 1 alpha increases serum leptin concentrations in humans.
Leptin, the protein product of the ob gene, regulates appetite and body weight in animals. Endotoxin and cytokines, induced by endotoxin, interleukin (IL) 1 and tumor necrosis factor, increase expression of leptin in mice and hamsters. We measured serum leptin concentrations in patients with cancer before and after administration of recombinant human IL-1 alpha. Fourteen patients received IL-1 alpha at one of three dose levels (0.03, 0.1, or 0.3 microgram/kg.day) for 5 days. Serum leptin concentrations increased in all but two patients within 24 h after the first dose. The increase in leptin was correlated directly with IL-1 alpha dose (P = 0.0030). Despite continued administration of IL-1 alpha, serum leptin concentrations returned to pretreatment levels by day 5 of therapy. An increase in serum leptin concentrations may be one mechanism by which anorexia is induced by IL-1 alpha. However, tachyphylaxis of the leptin response suggests that other mechanisms also are involved.


Optimal burst duration during a facilitated quadriceps femoris contraction.
To determine the most efficient burst duty cycle for eliciting an involuntary quadriceps femoris contraction in healthy subjects. This information will allow clinicians to make an informed decision about the optimal burst duty cycle based upon a specific treatment goal. The logical goal for such a treatment choice is to enhance motor unit recruitment in an effort to maintain postoperative or postinjury strength, when voluntary contractions may be less effective. Single-group and 5-measures design. All tests were performed in a university laboratory. Forty-eight healthy subjects (27 men and 21 women; mean age, 26.4 +/- 8.5 years) performed a maximal voluntary isometric contraction (MVIC) on an isokinetic device and received neuromuscular electrical stimulation (NMES) at 5 different burst duty cycles. Subjects first performed an MVIC for knee extension on an isokinetic dynamometer at 60 degrees of knee flexion. NMES surface electrodes were applied to the quadriceps muscle of each subject's dominant leg. The values for the NMES were 2500-Hz carrier frequency, 50-bursts-per-second treatment frequency, amplitude increased to maximum tolerance, and burst duty cycle set to each of the 5 comparison values. The peak isometric force generated by each of the 5 nonvolitional contractions was recorded, along with the maximal charge per burst tolerated by each subject. Force generated was described as percentage of MVIC. Efficiency was the amount of force per burst charge. The mean MVIC achieved by the subjects was 553.8 newtons (N). The average force per burst charge generated at 10% burst duty cycle was 132.9 N; at 30%, 104.2 N; at 50%, 93.1 N; at 70%, 52.9 N; and at 90%, 41.3 N. The average efficiency (force per millicoulombs [mC]) at 10% burst duty cycle was the highest at 6.49 N/mC and at 90% was the lowest at 1.05 N/mC. A burst duty cycle of 10% was the most efficient ratio of burst duration to interburst interval duration for eliciting the strongest muscle contraction. Use of this preferred duty cycle enabled only 8 of 48 subjects (16.6%) to achieve 60% MVIC within 1 trial in 1 session of NMES. Twenty-five subjects (52.0%) were able to achieve at least 10% of the MVIC in the same trial period.


Characterization and COD fractionation of domestic wastewaters.
Results of a comprehensive study are reported for wastewater characterization in relation to modelling and design of biological nutrient removal systems for the Metropolitan Area of Istanbul. Domestic sewage quality was experimentally assessed in terms of major polluting parameters. Size distribution and calculation of significant ratios such as BOD5:COD and COD:N were used to evaluate the merit of candidate physical, chemical and biological treatment alternatives. COD fractionation was effected to assess biological treatability and to yield the necessary process components to the recent modelling approaches.


On the inter-conversion between Hermite and Laguerre local image expansions.
The nice relationship existing among the Hermite-Gauss and the Laguerre-Gauss image expansions, whose basis functions span the same signal space, is investigated. As a result, a novel efficient method for Cartesian to polar coordinate inter-conversion, especially suited for dedicated hardware realization, is proposed. Applications to local image rotation, based on the simple steerability of the Laguerre-Gauss expansion, and to local image analysis, based on Gaussian derivatives, are considered in detail. A possible fixed-point realization of the proposed inter-conversion scheme is discussed.


Interrelated changes in parental stress, parenting, and coparenting across the onset of the COVID-19 pandemic.
Parental stress is a known risk factor for coercive parenting and for lower coparenting quality. In the present study, we examined whether and how changes in parental stress of mothers and fathers from the pre-COVID-19 period (T1) into the height of the first lockdown in the Netherlands (T2) were linked to changes in coercive parenting of mothers and fathers and to changes in coparenting quality. A total of 96 families (46.9% lower or medium and 53.1% higher educational background), with mother, father, and child (53.1% girls; T1: M age = 3.44 years, SD = 0.32; T2: M age = 4.72 years, SD = 0.61) participated. To examine interrelations between parental stress (reported using the Parental Stress Scale), coparenting, and coercive parenting (both reported using the Parenting And Family Adjustment Scales), a multivariate Latent Change Score (LCS) model was employed. Higher initial levels of parental stress were associated with higher initial levels of coercive parenting and lower initial levels of coparenting quality. Similarly, stronger increases in parental stress were associated with stronger increases in coercive parenting and with stronger decreases in coparenting quality. Directions of associations and effect sizes were similar for mothers and fathers in all analyses. The results from the present study indicate the importance of a family systems perspective in prevention and intervention programs. Promotion of systematic family-based preventive and intervention activities by the government might support families during challenging times, as during the novel COVID-19 pandemic. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Adult gaze influences infant attention and object processing: implications for cognitive neuroscience.
Infants follow others' gaze toward external objects from early in ontogeny, but whether they use others' gaze in processing information about objects remains unknown. In Experiment 1, 4-month-old infants viewed a video presentation of an adult gazing toward one of two objects. When presented with the same objects alone a second time, infants looked reliably less at the object to which the adult had directly gazed (cued object). This suggests that the uncued object was perceived as more novel than the object previously cued by the adult's gaze. In Experiment 2, adult gaze was not directed towards any object. In this control experiment, infants looked at both objects equally in the test phase. These findings show that adult eye gaze biases infant visual attention and information processing. Implications of the paradigm for cognitive neuroscience are presented and the results are discussed in terms of neural structures and change over ontogeny.


Electrostatic Impact of Brefeldin A on Thiocyanate Probes Surrounding the Interface of Arf1-BFA-ARNO4M, a Protein-Drug-Protein Complex.
Protein-protein interactions regulate many cellular processes, making them ideal drug candidates. Design of such drugs, however, is hindered by a lack of understanding of the factors that contribute to the interaction specificity. Specific protein-protein complexes possess both structural and electrostatic complementarity, and while structural complementarity of protein complexes has been extensively investigated, fundamental understanding of the complicated networks of electrostatic interactions at these interfaces is lacking, thus hindering the rational design of orthosterically binding small molecules. To better understand the electrostatic interactions at protein interfaces and how a small molecule could contribute to and fit within that environment, we used a model protein-drug-protein system, Arf1-BFA-ARNO4M, to investigate how small molecule brefeldin A (BFA) perturbs the Arf1-ARNO4M interface. By using nitrile probe labeled Arf1 sites and measuring vibrational Stark effects as well as temperature dependent infrared shifts, we measured changes in the electric field and hydrogen bonding at this interface upon BFA binding. At all five probe locations of Arf1, we found that the vibrational shifts resulting from BFA binding corroborate trends found in Poisson-Boltzmann calculations of surface potentials of Arf1-ARNO4M and Arf1-BFA-ARNO4M, where BFA contributes negative electrostatic potential to the protein interface. The data also corroborate previous hypotheses about the mechanism of interfacial binding and confirm that alternating patches of hydrophobic and polar interactions lead to BFA binding specificity. These findings demonstrate the impact of BFA on this protein-protein interface and have implications for the design of other interfacial drug candidates.


Characterization of BRCA1/2 mutations in patients with family history of breast cancer in Armenia.
Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives. Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool. Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations. Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers.


Tumor angiogenic factor and human skin tumors.
A transparent acrylic hamster cheek-pouch chamber was used to investigate the elaboration of a tumor angiogenic factor (TAF) by human cutaneous neoplasms; direct tumor implantations, transfilter diffusion, and soluble tumor extracts were used in the study. A diffusible and filterable TAF was extracted from cutaneous tumors and produced distinctive patterns of sequential vasodilatation, tortuosity, and neovascular proliferation in the cheek-pouch membrane. Malignant human neoplasms (eg, melanoma, basal cell epithelioma, squamous cell carcinoma, lymphoma) produced striking neovascularization; vascular tumors (eg, Kaposi sarcoma, pyogenic granuloma, vascular histiocytoma) stimulated dramatic hyperemia and ectasia. Angiogenesis was conspicuously absent after implantation of control materials and nevoid or normal cutaneous components (with the exception of epidermis). Tumor angiogenic factor appears to induce direct stimulation of endothelial cell mitosis and may be essential for survival of nutritionally ravenous neoplastic tissues. The interference with TAF has therapeutic implications.


The spatiotemporal control of expert tennis players when returning first serves: A perception-action perspective.
The aim of the current experiment was to examine the spatiotemporal control of expert tennis players while executing first service returns within a representative experimental setting. We recruited and tested 12 male expert tennis players in hard courts. A comprehensive analysis of the timing (eleven temporal variables analysed at 300 Hz) and performance success of the return actions were carried out, while simultaneously considering task constraints such as the accuracy and the speed of the serves. Temporal organisation of return actions were scaled relative to the server's racket-ball contact (5 ms), an adaptation of fly-time of the split-step, which resulted in consistent landings (133 ms), and initiation of lateral movements towards the ball - with no response errors - after the server's stroke (around 177 ms). Poorer returns occurred when responding to accurate serves accompanied by late trunk movements towards the ball. Returners scaled the timing of the response to the unfolding action of the serve in order to support both spatial and temporal accuracy. These novel findings highlight the significance of the study of fast-ball sports in representative settings and offer further detail on the spatiotemporal control of skilful perception-action.


The complete genome analysis of Crimean-Congo hemorrhagic fever virus isolated in Turkey.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne disease with high mortality rates in humans. The distribution of CCHFV includes over 30 countries in Asia, the Middle East, southeastern Europe, and Africa. It was first recognized in Turkey in 2002, with an increasing number of cases reported between 2002 and 2009. Recent analysis of complete genome sequences of CCHFV isolates has revealed that the genomic plasticity of the virus is surprisingly high for an arthropod-borne virus. We have determined the complete nucleotide and deduced amino acid sequences of strain CCHFV Turkey-Kelkit06 isolated from the blood of a patient in an endemic region of Turkey in 2006. The complete sequence length of the CCHFV Turkey-Kelkit06 strain is 19,186 nt, consisting of a 1673 nt S segment, a 5364 nt M segment, and a 12,149 nt L segment. Based on the analysis of S, M, and L segments, CCHFV Turkey-Kelkit06 clustered in Group V, which represents the Europe/Turkey geographic lineage. Although glycoproteins encoded by the M gene are the most variable part of the CCHFV Turkey-Kelkit06 strain, some functional domains of the glycoproteins are well conserved. Here, we report the complete sequence and genome organization of the CCHFV Turkey-Kelkit06 strain and its phylogenetic relationship to other strains of CCHFV. Collecting data on viral sequences among isolates from CCHF epidemics may provide valuable information regarding the molecular basis of the epidemic potential of the virus.


Preventive effect of hydrotalcite on gastric mucosal injury in rats induced by taurocholate.
To study the preventive effect of hydrotalcite on gastric mucosal injury in rat induced by taurocholate, and to investigate the relationship between the protective mechanism of hydrotalcite and the expression of trefoil factor family 2 (TFF2) mRNA and c-fos protein. Forty five male Wistar rats were randomly divided into hydrotalcite group, ranitidine group and control group. Gastric mucosal injury was induced by introgastric acidified taurocholate. OD value of TFF2 mRNA expression in gastric mucous cells was determined by hybridization and computer image analysis system. OD value of c-fos protein expression in gastric mucous cells was measured by immunohistochemistry and computer image analysis system. The gross mucosal injury index in hydrotalcite group was significantly lower than that in ranitidine group and control group (8.60+/-2.20 vs 16.32+/-4.27, 29.53+/-5.39; P<0.05, P<0.01). The expression level of TFF2 mRNA in hydrotalcite group was markedly higher than that in ranitidine group and control group (0.56+/-0.09 vs 0.30+/-0.05, 0.28+/-0.03, P<0.05). The OD value of c-fos protein in hydrotalcite group was higher than that in ranitidine group and control group (0.52+/-0.07 vs 0.31+/-0.04, 0.32+/-0.05, P<0.05). Hydrotalcite can protect gastric mucosal injury in rats induced by taurocholate, which may be related to the increased expression of TFF2 and c-fos protein.


[Atrial fibrillation and heart failure].
Atrial fibrillation (AF) and heart failure (HF) are two conditions widespread on the population, especially in elderly people. When AF and HF coexist in the same patient, as frequently happens, they trigger a vicious circle of mutual influence, who dramatically hesitates in lower quality of life and in increased mortality. The relationship between AF and HF is long and vigorously investigated: it is an ever-changing field of knowledge because alongside well known and proven results, especiallythe pathophysiological ones, there are new horizons of research since many aspects are still obscure. Hence, this limit is reflected in the complexity of the combined management of AF and HF in clinical practice. It also explains an ominous prognosis despite significant therapeutic advances. In this review we go over again the well-established knowledge about the pathophysiology binder HF and AF; we provide some epidemiological, clinical and therapeutic informations, we also highlight the new acquisitions, the new research areas and, finally, the still unresolved questions.


Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S.
D2 receptor null mutant (Drd2(-/-)) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain, and D2S the autoreceptor that regulates the activity of dopamine neurons and dopamine synthesis and release. Because constitutive genetic deletion of the D2 or D2L receptor may cause compensatory changes that influence functional outcomes, our approach is to identify aspects of the abnormal phenotype of a Drd2(-/-) mouse that can be normalized by virus-mediated D2 receptor expression. Drd2(-/-) mice are deficient in basal and methamphetamine-induced locomotor activation and lack D2 receptor agonist-induced activation of G protein-regulated inward rectifying potassium channels (GIRKs) in dopaminergic neurons. Here we show that virus-mediated expression of D2L in the nucleus accumbens significantly restored methamphetamine-induced locomotor activation, but not basal locomotor activity, compared to mice receiving the control virus. It also restored the effect of methamphetamine to decrease time spent in the center of the activity chamber in female but not male Drd2(-/-) mice. Furthermore, the effect of expression of D2S was indistinguishable from D2L. Similarly, virus-mediated expression of either D2S or D2L in substantia nigra neurons restored D2 agonist-induced activation of GIRKs. In this acute expression system, the alternatively spliced forms of the D2 receptor appear to be equally capable of acting as postsynaptic receptors and autoreceptors.


Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy.
To characterize the abnormal B-cell response to glucose in type II diabetes, five diet-treated diabetic and six weight-matched non-diabetic subjects were studied using the hyperglycemic clamp technique on three separate days at glycemic levels of 7.5, 10 and 15 mmol/L for 150 minutes with assessment of plasma insulin and C-peptide responses. To reduce possible secondary effects of hyperglycemia, diabetic subjects on a weight-maintaining diet were chosen who had only a slight elevation of the fasting plasma glucose, mean 6.0 mmol/L. They had a normal time-course of both first- and second-phase responses, but both were impaired at each glucose clamp concentration. The first-phase and second-phase C-peptide responses of the diabetic subjects were similarly reduced to mean 49% and 59% of normal, respectively, and the first- and second-phase insulin responses were also reduced to mean 39% and 44% of normal, respectively. The ratio of second- to first-phase plasma C-peptide responses were similar in the diabetic and normal subjects, median 1.6 and 1.5, respectively, as were the same ratios for the insulin responses, 1.4 and 1.1, respectively. The previously described selective reduction of the first-phase response in type II diabetes may be partly a function of the bolus intravenous glucose tests used, in which impaired glucose tolerance in the diabetics gave a greater glycemic stimulus to the second phase than in normal subjects, and partly secondary to long-term hyperglycemia. The diabetic subjects were re-studied after treatment with a sulphonylurea, gliclazide, with a normal fasting plasma glucose, mean 5.1 mmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)


Vortioxetine improves rapid eye movement sleep behavior disorder: A case report.
Rapid eye movement sleep behavior disorder (RBD) is a kind of sleep disturbance characterized by a loss of normal paralysis of REM sleep with dream enactment behavior during REM sleep. The pharmacotherapy options for treating RBD are limited and the use of antidepressants remains controversial. Further, the role of vortioxetine in RBD has not been evaluated so far. A 72-year-old woman presented with recurrent peculiar behaviors such as shouting, punching, kicking or even walking around her bedroom during sleep for over 3 years. Clinical examinations and polysomnography indicated the diagnosis of RBD. The patient received treatment with paroxetine and melatonin for 1 year and then paroxetine was discontinued and vortioxetine was initiated in a daily dose of 10 mg. Treatment with paroxetine and melatonin for one year was ineffective. A trial of vortioxetine 10 mg per day over 3 months resulted in significant clinical improvement. To our knowledge, this is the first reported case of effective treatment of RBD with vortioxetine. Well-designed studies with large samples are needed to verify the clinical benefits.


Quality indicators of hip fracture management. A systematic review.
To identify standards and quality indicators of hip fracture management from the medical literature. We conducted a "systematic review" on the topic of quality indicators of hip fracture management using PubMed database, during 15 years from 2001 to 2015. The collected publications were studied by two readers to extract the different quality indicators of hip fracture management. These indicators were stratified according to their type (process or outcome) and to the time of health care (pre, per or post-operative). A total of 41 articles were included in the study: The analysis of these articles highlighted a predominance of Anglo-Saxon papers, an increasing rate of publication over time, a dominance of evaluative studies and a multiplicity of guidelines. A total of 46 quality indicators were identified through these articles. Two third were classified as procedural items and 60% were about post-operative hip fracture management. The most assessed indicators and standards, among those related to the preoperative care, were time to surgery (34%) and patient clinical condition assessment (11%). During the operation time, the most assessed indicator was the proportion of patients who have had spinal anesthesia (73%). For the postoperative care, the most common indicators and standards were length of hospital stay (12%), osteoporosis treatment prescription (8%), mattresses use to prevent pressure ulcer (7%), pressure sores occurring (7%) and in hospital mortality (7%). This systematic review allowed to identify the main indicators recommended to evaluate the management of hip fracture. The continuous monitoring of these indicators should be generalized in maghrebian countries using strategic dashboards in all hospitals and clinics treating this pathology.


Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice.
Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.


Square channels formed by a peptide derived from transthyretin.
High-resolution structures of peptide supramolecular assemblies are key to understanding amyloid diseases and designing peptide-based materials. This paper explores the supramolecular assembly of a macrocyclic β-sheet peptide derived from transthyretin (TTR). The peptide mimics the β-hairpin formed by the β-strands G and H of TTR, which form the interface of the TTR tetramer. X-ray crystallography reveals that the peptide does not form a tetramer, but rather assembles to form square channels. The square channels are formed by extended networks of β-sheets and pack in a "tilted windows" pattern. This unexpected structure represents an emergent property of the peptide and broadens the scope of known supramolecular assemblies of β-sheets.


Type 3 inositol trisphosphate receptors in RINm5F cells are biphasically regulated by cytosolic Ca2+ and mediate quantal Ca2+ mobilization.
There are three subtypes of mammalian Ins(1,4,5)P(3) (InsP(3)) receptor, each of which forms an intracellular Ca(2+) channel. Biphasic regulation of InsP(3) receptors by cytosolic Ca(2+) is well documented in cells expressing predominantly type 1 or type 2 InsP(3) receptors and might contribute to the regenerative recruitment of Ca(2+) release events and to limiting their duration in intact cells. The properties of type 3 receptors are less clear. Bilayer recording from InsP(3) receptors of RIN-5F cells, cells in which the InsP(3) receptors are likely to be largely type 3, recently suggested that the receptors are not inhibited by Ca(2+) [Hagar, Burgstahler, Nathanson and Ehrlich (1998) Nature (London) 296, 81-84]. By using antipeptide antisera that either selectively recognized each InsP(3) receptor subtype or interacted equally well with all subtypes, together with membranes from Spodoptera frugiperda (Sf9) cells expressing only single receptor subtypes to calibrate the immunoblotting, we quantified the relative levels of expression of type 1 (17%) and type 3 (77%) InsP(3) receptors in RINm5F cells. In unidirectional (45)Ca(2+) efflux experiments from permeabilized RINm5F cells, submaximal concentrations of InsP(3) released only a fraction of the InsP(3)-sensitive Ca(2+) stores, indicating that responses to InsP(3) are quantal. Increasing the cytosolic free [Ca(2+)] ([Ca(2+)](i)) from approx. 4 to 186 nM increased the sensitivity of the Ca(2+) stores to InsP(3): the EC(50) decreased from 281+/-15 to 82+/-2 nM. Further increases in [Ca(2+)](i) massively decreased the sensitivity of the stores to InsP(3), by almost 10-fold when [Ca(2+)](i) was 2.4 microM, and by more than 3000-fold when it was 100 microM. The inhibition caused by 100 microM Ca(2+) was fully reversed within 60 s of the restoration of [Ca(2+)](i) to 186 nM. The effect of submaximal InsP(3) concentrations on Ca(2+) mobilization from permeabilized RINm5F cells is therefore biphasically regulated by cytosolic Ca(2+). We conclude that type 3 InsP(3) receptors of RINm5F cells mediate quantal Ca(2+) release and they are biphasically regulated by cytosolic Ca(2+), either because a single type 1 subunit within the tetrameric receptor confers the Ca(2+) inhibition or because the type 3 subtype is itself directly inhibited by Ca(2+).


Biogeography of Cyanobacterial isiA Genes and Their Link to Iron Availability in the Ocean.
The cyanobacterial iron-stress-inducible isiA gene encodes a chlorophyll-binding protein that provides flexibility in photosynthetic strategy enabling cells to acclimate to low iron availability. Here, we report on the diversity and abundance of isiA genes from 14 oceanic stations encompassing large natural gradients in iron availability. Synechococcus CRD1 and CRD2-like isiA genes were ubiquitously identified from tropical and subtropical waters of the Pacific, Atlantic, and Indian Oceans. The relative abundance of isiA-containing Synechococcus cells ranged from less than 10% of the total Synechococcus population in regions where iron is replete such as the North Atlantic subtropical gyre, to over 80% in low-iron but high-nitrate regions of the eastern equatorial Pacific. Interestingly, Synechococcus populations in regions with both low iron and low nitrate concentrations such as the subtropical gyres in the North Pacific and South Atlantic had a low relative abundance of the isiA gene. Indeed, fitting our data into a multiple regression model showed that ∼80% of the variation in isiA relative abundances can be explained by nitrate and iron concentrations, whereas no other environmental variables (temperature, salinity, Chl a) had a significant effect. Hence, isiA has a predictable biogeographical distribution, consistent with the perceived biological role of IsiA as an adaptation to low-iron conditions. Understanding such photosynthetic strategies is critical to our ability to accurately estimate primary production and map nutrient limitation on global scales.


Cerebral Salt Wasting in Traumatic Brain Injury Is Associated with Increased Morbidity and Mortality.
In the setting of cerebral injury, cerebral salt wasting (CSW) is a potential cause of hyponatremia, which contributes to adverse effects and mortality. The primary objective of this study was to evaluate the clinical outcomes of severe traumatic brain injury (TBI) patients complicated by CSW. A retrospective data analysis was performed on data collected from patients with TBI with an abbreviated injury scale (AIS) greater than 3. Data was divided into 2 groups of patients with CSW and those without. The primary endpoint was incidence of adverse effects of CSW in regard to injury severity score (ISS), hospital length of stay (HLOS), ventilator days, ICU length of stay (ICU LOS) and survival to discharge. Data was analyzed using a one-way analysis of variance (ANOVA). A total of 310 consecutive patients with severe head injury (anatomic injury score 3 or greater) were evaluated over a 3-year period. A total of 125 of the 310 patients (40%) were diagnosed with cerebral salt wasting as defined by hyponatremia with appropriate urinary output and salt replacement. Patients with CSW had poorer outcomes in regard to ISS (21.8 vs 14.2, p<0.0001), HLOS (14.1 vs 3.5, p<0.0001), ventilator days (5.0 vs 0.45, p<0.0001), ICU LOS (8.5 vs 1.6, p<0.0001), and survival to discharge (88% vs 99%, p<0.0001). Common adverse effects of CSW were noted in this study. Patients with TBI have a predilection towards development of CSW and consequently have poorer outcomes including increased morbidity and mortality. Data is sparse on the duration of CSW and degree of hyponatremia over time. Larger, comparative studies need to be performed to investigate the hyponatremic patient population and the clinical outcomes of those who present with CSW.


PPD-, PWM-, and PHA-induced interferon in stable multiple sclerosis: association with HLA-Dw2 antigen and clinical variables.
Interferon production after stimulation of lymphocytes with purified protein derivative, pokeweed mitogen, and phytohemagglutinin was studied in 39 patients with stable multiple sclerosis (MS) and 39 age- and sex-matched controls. Stable MS patients produced less interferon, and the number of subjects producing undetectable amounts of interferon was higher in the MS group (11/39) than in the control group (2/39). A tendency toward an association between low interferon production and HLA-Dw2 antigen was found in MS patients. There was no clear-cut correlation between interferon production and the duration of disease or disability of the patients. Although there was no systematic correlation of age with interferon production, patients older than 55 years tended to be very poor interferon producers.


The use of mifepristone in abortion associated with an increased risk of uterine leiomyomas.
To investigate the association between widespread use of mifepristone in abortions and risk of uterine leiomyomas.We conducted a case-control study of 305 patients with uterine leiomyomas between January 2011 and July 2012; 311 women with ordinary vaginitis were selected as controls during the same period. Data were collected by questionnaires (including past history, life history, menstruation history, reproductive history, abortion history, the use of mifepristone, and uterine leiomyomas risk factors) and calculated by univariate and multivariate conditional logistic regression analyses; odds ratios and its 95% confidence interval were calculated to estimate the risk for uterine leiomyomas.Abortion with mifepristone was one of the risk factors for uterine leiomyomas, and the risk increased with increasing frequency of mifepristone use. Family history of uterine leiomyomas, body mass index, age at menarche, number of full-term delivery, and medical abortion history were also correlated with uterine leiomyomas.The use of mifepristone in abortion will increase the risk to develop uterine leiomyomas.


Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma.
Carbonic anhydrase enzymes (CAs) are universally involved in many fundamental physiological processes, including acid base regulation and fluid formation and movement. In glaucoma patients, CA inhibitors are very effective in lowering intraocular pressure by reducing the rate of aqueous humour secretion mediated by the CAs in the ciliary epithelium. In this work, we investigated the expression and tissue distribution of two recently discovered CA genes CA9 (CAIX) and CA12 (CAXII) in fetal, neonatal, and adult human eyes with and without glaucoma. CAIX and CAXII expression in 16 normal and 10 glaucomatous eyes, and in cultured non-pigmented ciliary epithelial cells (NPE) from normal and glaucoma eye donors was assessed by immunostaining. In addition, northern blot hybridisation was performed to assess expression of CA4, CA9, and CA12 mRNA in cultured NPE cells from normal and glaucoma donors. CAXII was localised primarily to the NPE with its expression prominent during embryonic eye development but which decreased significantly in adults. CAIX expression in the NPE was very low. The epithelium of cornea and lens occasionally expressed both enzymes at low levels during development and in adult eye, and no expression was detected in the retina. The NPE from glaucoma eyes expressed higher levels of CAXII, but not CAIX, in comparison with normal eyes. This expression pattern was retained in cultured NPE cell lines. NPE cells from a glaucoma patient showed a five-fold increase in the CA12 mRNA level with no detectable expression of CA9 mRNA. Also, no expression of the CA4 gene encoding a GPI anchored plasma membrane protein was detected on these northern blots. Transmembrane CAIX and CAXII enzymes are expressed in the ciliary cells and, thus, may be involved in aqueous humour production. CA12 may be a targeted gene in glaucoma.


Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial.
The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.


Neurotrophic regulation of retinal ganglion cell synaptic connectivity: from axons and dendrites to synapses.
This review highlights important events during the morphological development of retinal ganglion cells (RGCs), focusing on mechanisms that control axon and dendritic arborization as a means to understand synaptic connectivity with special emphasis on the role of neurotrophins during structural and functional development of RGCs. Neurotrophins and their receptors participate in the development of visual connectivity at multiple levels. In the visual system, neurotrophins have been shown to exert various developmental influences, from guiding the morphological differentiation of neurons to controlling the functional plasticity of visual circuits. This review article examines the role of neurotrophins, and in particular of BDNF, during the morphological development of RGCs, and discusses potential interactions between activity and neurotrophins during development of neuronal connectivity.


Omega-3 fatty acid supplementation for cystic fibrosis.
Studies suggest that a diet rich in omega-3 essential fatty acids may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. This is an updated version of a previously published review. To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality and to identify any adverse events associated with supplementation. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of last search: 01 April 2020. We also searched online study registries and contacted authors. Date of last search: 12 February 2020. Randomised controlled trials in people with cystic fibrosis comparing omega-3 fatty acid supplements with placebo. Two authors independently selected studies for inclusion, extracted data and assessed the risk of bias of the studies. The quality of the evidence was assessed using GRADE. The searches identified 23 studies; five studies with 106 participants (children and adults) were included; duration of studies and interventions differed. Two studies compared omega-3 fatty acids to olive oil for six weeks; one study compared omega-3 fatty acids and omega-6 fatty acids to control capsules (customised fatty acid blends) for three months; one study compared a liquid dietary supplement containing omega-3 fatty acids to one without for six months; and one study compared omega-3 fatty acids to a placebo for 12 months. Three studies had a low risk of bias for randomisation, but the risk was unclear in the remaining two studies; all studies had an unclear risk of bias for allocation concealment. Three of the studies adequately blinded participants; the risk of bias for selective reporting was high in one study and unclear for four studies. Two studies reported the number of respiratory exacerbations. At three months, one study (43 participants) reported no change in antibiotic usage. At 12 months the second study (15 participants) reported a reduction in the number of pulmonary exacerbations and cumulative antibiotic days in the supplement group compared to the previous year (no data for the control group); very low-quality evidence means we are unsure whether supplementation has any effect on this outcome. With regards to adverse events, one six-week study (12 participants) reported no difference in diarrhoea between omega-3 or placebo capsules; the very low-quality evidence means we are unsure if supplementation has any effect on this outcome. Additionally, one study reported an increase in steatorrhoea requiring participants to increase their daily dose of pancreatic enzymes, but three studies had already increased pancreatic enzyme dose at study begin so as to reduce the incidence of steatorrhoea. One study (43 participants) reported stomach pains at three months (treatment or control group not specified). One six-week study (19 participants) reported three asthma exacerbations leading to exclusion of participants since corticosteroid treatment could affect affect essential fatty acid metabolism. Four studies reported lung function. One six-week study (19 participants) reported an increase in forced expiratory volume in one second (FEV1) (L) and forced vital capacity (FVC) (L), but the very low-quality evidence means we are unsure if supplementation has any effect on lung function. The remaining studies did not report any difference in lung function at three months (unit of measurement not specified) or at six months and one year (FEV1 % predicted and FVC % predicted). No deaths were reported in any of the five studies. Four studies reported clinical variables. One study reported an increase in Schwachman score and weight alongside a reduction in sputum volume with supplementation compared to placebo at three months (data not analysable). However, three studies reported no differences in either weight at six weeks, in body mass index (BMI) standard deviation (SD) score at six months (very low-quality evidence) or BMI Z score at 12 months. Three studies reported biochemical markers of fatty acid status. One study showed an increase from baseline in both EPA and DHA content of serum phospholipids in the omega-3 group compared to placebo at three months and also a significant decrease in n-6/n-3 ratio in the supplement group compared to placebo; since the quality of the evidence is very low we are not certain that these changes are due to supplementation. One six-month cross-over study showed a higher EPA content of the neutrophil membrane in the supplement group compared to the placebo group, but, no difference in DHA membrane concentration. Furthermore, the leukotriene B4 to leukotriene B5 ratio was lower at six months in the omega-3 group compared to placebo. A one-year study reported a greater increase in the essential fatty acid profile and a decrease in AA levels in the treatment arm compared to placebo. This review found that regular omega-3 supplements may provide some limited benefits for people with cystic fibrosis with relatively few adverse effects: however, the quality of the evidence across all outcomes was very low. The current evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes when providing omega-3 supplementation or olive oil placebo capsules. More research is required to determine the exact dose of pancreatic enzyme required.


Comparison of auditory spatial bisection and minimum audible angle in front, lateral, and back space.
Although vision is important for calibrating auditory spatial perception, it only provides information about frontal sound sources. Previous studies of blind and sighted people support the idea that azimuthal spatial bisection in frontal space requires visual calibration, while detection of a change in azimuth (minimum audible angle, MAA) does not. The influence of vision on the ability to map frontal, lateral and back space has not been investigated. Performance in spatial bisection and MAA tasks was assessed for normally sighted blindfolded subjects using bursts of white noise presented frontally, laterally, or from the back relative to the subjects. Thresholds for both tasks were similar in frontal space, lower for the MAA task than for the bisection task in back space, and higher for the MAA task in lateral space. Two interpretations of the results are discussed, one in terms of visual calibration and the use of internal representations of source location and the other based on comparison of the magnitude or direction of change of the available binaural cues. That bisection thresholds were increased in back space relative to front space, where visual calibration information is unavailable, suggests that an internal representation of source location was used for the bisection task.


Mapping and fitting the peripheral benzodiazepine receptor binding site by carboxamide derivatives. Comparison of different approaches to quantitative ligand-receptor interaction modeling.
The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921) has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PBR binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PBR affinity similar to that shown by 1 and the presence of a basic N-ethyl-N-benzylaminomethyl group in 3-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to ligand-receptor interactions. Molecular descriptors which explicitly account for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments.